title: Rosuvastatin inhibits human airway smooth muscle cells mitogenic response to eicosanoid contractile agents.
abstract: BACKGROUND
  The concept of permanent narrowing of the airways resulting from chronic inflammation and fibrosis is called remodeling and is a common feature of asthma and chronic obstructive pulmonary disease (COPD). The eicosanoid contractile agents thromboxane A(2) (TxA(2)) and cysteinyl-leukotriene D(4) (LTD(4)) are among the recognized mitogens for human airway smooth muscle (ASM) cells. Statins are known to possess anti-inflammatory and immunomodulatory properties that are independent on their cholesterol-lowering effects and may result in clinical lung benefits. Rosuvastatin is the last agent of the lipid-lowering drugs to be introduced and experimental evidence indicates that it possess favorable pleiotropic effects in the cardiovascular and nervous systems. Yet, no data is available in the literature regarding its effects on human airway remodeling. The present study was aimed at examining the effect of rosuvastatin and the involvement of prenylated proteins in the response of human ASM cells to serum, epidermal growth factor (EGF) and eicosanoid contractile mitogens that activate TxA(2) prostanoid and LTD(4) receptors.
  
  
  METHODS
  Cell growth was assessed by nuclear incorporation of [(3)H]thymidine in human ASM cells serum-starved and then stimulated for 48 h in MEM plus 0.1% BSA containing mitogens in the absence and presence of modulators of the mevalonate and prenylation pathways.
  
  
  RESULTS
  We found that rosuvastatin dose-dependently inhibited serum-, EGF-, the TxA(2) stable analog U46619-, and LTD(4)-induced human ASM cells growth. All these effects were prevented by pretreatment with mevalonate. Addition of the prenylation substrates farnesol and geranylgeraniol reversed the effect of rosuvastatin on EGF and U46619, respectively. Interestingly, only mevalonate showed restoration of cell growth following rosuvastatin treatment in LTD(4) and LTD(4) plus EGF treated cells, suggesting a possible involvement of both farnesylated and geranylgeranylated proteins in the cysteinyl-LT-induced cell growth.
  
  
  CONCLUSIONS
  The hydrophilic statin rosuvastatin exerts direct effects on human ASM cells mitogenic response in vitro by inhibiting prenylation of signaling proteins, likely small G proteins. These findings are consistent with previous observed involvement of small GTPase signaling in EGF- and U46619-induced human airway proliferation and corroborate the recent interest in the potential clinical benefits of statins in asthma/COPD.
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy. Electronic address: valerie.capra@unimi.it.
authors.forename: Valérie
authors.initials: V
authors.lastname: Capra
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy. Electronic address: genrico.rovati@unimi.it.
authors.forename: G Enrico
authors.initials: GE
authors.lastname: Rovati
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D056151:Airway Remodeling / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000378:metabolism; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D008934:Mitogens / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D012710:Serum Albumin, Bovine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D015777:Eicosanoids; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008934:Mitogens; D011743:Pyrimidines; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D012710:Serum Albumin, Bovine; D004815:Epidermal Growth Factor; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000068718:Rosuvastatin Calcium; C083169:leukotriene D4 receptor; D008798:Mevalonic Acid
keywords: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; 3-hydroxy-3-methylglutaryl-coenzyme-A; ASM; Airway smooth muscle; Asthma; BSA; COPD; Cysteinyl-leukotrienes; EGF; FBS; GGTase I; HMG-CoA; LTD(4); MEM; ROS; Remodeling; Thromboxane; TxA(2); airway smooth muscle; bovine serum albumin; chronic obstructive pulmonary disease; cysteinyl-leukotriene D(4); epidermal growth factor; fetal bovine serum; geranylgeranyltransferase I; modified Eagle's medium; reactive oxygen species; thromboxane A(2)